Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

• the present invention relates to a process for preparing [3-chloro-2-[3-[2-[1-(2-chloroacetyl)-4-piperidyl]thiazol-4-yl]-4,5-dihydroisoxazol-5-yl]phenyl] methanesulfonate.
• [3-chloro-2-[3-[2-[1-(2-chloroacetyl)-4-piperidyl]thiazol-4-yl]-4,5-dihydroisoxazol-5-yl]phenyl] methanesulfonate is an intermediate of fluoxapiprolin, which is a fungicide for control of oomycetes known from WO 2012/025557 .
• WO 2015/181097 discloses a process for preparing [3-chloro-2-[3-[2-[1-(2-chloroacetyl)-4-piperidyl]thiazol-4-yl]-4,5-dihydroisoxazol-5-yl]phenyl] methanesulfonate (compound of the formula (I)) via a chloroacetyl-substituted compound of the formula (II), which is reacted with piperidine-4-carbothioamide (III) in presence of hydrochloric acid and ethanol in a Hantzsch reaction to give a piperidinium salt of the formula (IV). The piperidinium salt of the formula (IV) is then converted to the compound of the formula (I) by reaction with chloroacetylchloride in presence of tributylamine and tetrahydrofuran as solvent (see Scheme 1).
• step (a) of the process according to the invention the compound of formula (II) is reacted with the compound of formula (III) in presence of hydrogen chloride and an alcoholic solvent to give the hydrochloride salt of formula (IV).
• Suitable alcoholic solvents are methanol, ethanol, n-propanol (propanol), iso-propanol, n-butanol (butanol), iso-butanol, sec-butanol and tert-butanol.
• Preferred alcoholic solvents are isopropanol and ethanol. Most preferred is ethanol.
• the hydrogen chloride is used in form of hydrochloric acid, more preferably hydrochloric acid having a HCl concentration of at least 20 wt.%, more preferably at least 30 wt.%, and in particular at least 35 wt.%.
• step (a) is effected at temperatures of -20°C to + 120°C, preferably at temperatures of 20°C to +100°C, more preferably at 40°C to 80°C under standard pressure.
• the compound of formula (III) is first converted to the corresponding hydrochloride in presence of the alcoholic solvent, before the compound of formula (II) is added.
• the amount of hydrogen chloride used in step (a) is preferably within the range of from 1 mol to 3 mol, more preferably 1 mol to 2 mol, and most preferably 1 mol to 1.5 mol per 1 mol of the compound of formula (II).
• the amount of the compound of formula (III) used in step (a) is preferably within the range of from 1 mol to 3 mol, more preferably 1 mol to 2 mol, and most preferably 1 mol to 1.5 mol per 1 mol of the compound of formula (II).
• reaction time is not critical and may, according to the batch size and temperature, be selected within a range between a few minutes and several hours.
• a suitable reaction time is for example between 2 h and 10 h.
• step (b) of the process according to the invention the hydrochloride salt of the formula (IV) is reacted with chloroacetyl chloride in presence of a pyridine base, an aprotic solvent and an aromatic solvent having a boiling point of at least 160°C to give the compound of the formula (I).
• the amount of chloroacetyl chloride used in step (b) is preferably within the range of from 1 mol to 5 mol, more preferably 1.5 mol to 4 mol, and most preferably 1.5 mol to 2.5 mol per 1 mol of the compound of formula (IV).
• the reaction according to step (b) is preferably effected at temperatures of 0°C to +120°C, more preferably at temperatures of 20°C to 80°C, most preferably at 30°C to 60°C under standard pressure.
• reaction time is not critical and may, according to the batch size and temperature, be selected within a range between a few minutes and several hours.
• a suitable reaction time is for example between 1 h and 5h.
• the pyridine base is an alkyl pyridine base.
• Suitable alkyl pyridines which can be employed in the process according to the invention include the collidines, lutadines, picolines, the methylethyl pyridines, the diethyl pyridines, 2-isopropylpyridine, 2-propylpyridine, 2-methyl-3-propylpyridine, 2-ethyl-5-propylpyridine, 2-methyl-5-tert-butylpyridine, 2-ethyl-3-amylpyridine, 2-decylpyridine and 2-butyl-5-octylpyridine.
• Preferred pyridine bases are selected from the picolines, lutidines, collidines, methylethyl pyridines and diethyl pyridines. Most preferred is 2-methyl-5-ethyl-pyridine.
• the amount of pyridine base used is preferably within the range of from 1 mol to 20 mol, more preferably 2 mol to 10 mol, and most preferably 3 mol to 6 mol per 1 mol of the compound of formula (IV).
• Suitable polar aprotic solvents are ethers such as diethyl ether, methyl tert-butyl ether, dibutyl ether, ethylenglycoldimethylether, diethylenglycoldimethylether, methyltetrahydrofuran, tetrahydrofuran and 1,4-dioxane, ketones such as acetone, methyl ethyl ketone, methyl isopropyl ketone and methyl isobutyl ketone, esters such as methyl acetate, ethyl acetate and butyl acetate, nitriles, for example acetonitrile, propionitrile and butyronitrile, amides, for example dimethylformamide, dimethylacetamide and N-methylpyrrolidone, dimethyl sulphoxide, tetramethylenesulphone, hexamethylphosphoramide and DMPU.
• ethers such as die
• acetonitrile Especially preferred is acetonitrile.
• Suitable aromatic solvents having a boiling point of at least 160°C which can be employed in the process according to the invention include 1,3,5-trimethylbenzene (mesitylene), 1,2,3-trimethylbenzene, 1,2,4-trimethylbenzene, 1,2-dichlorobenzene, 1,3-dichlorobenzene, 1,4-dichlorobenzene, 1,2-dimethoxybenzene (veratrole), 1,3-dimethoxybenzene, 1,4-dimethoxybenzene, and mixtures thereof.
• the aprotic solvent and the aromatic solvent having a boiling point of at least 160°C are preferably used in a ratio by weight of from 10:1 to 1:5, more preferably 5:1 to 1:2, and most preferably 3:1 to 1:1.
• the aromatic solvent having a boiling point of at least 160°C is mesitylene.
• Polar aprotic solvent and mesitylene are preferably used in a ratio by weight of from 10:1 to 1:5, more preferably 5:1 to 1:2, and most preferably 3:1 to 1:1.
• the solvent is changed between steps (a) and (b) from alcoholic solvent to aprotic solvent by distillation.
• at least 95 wt.%, more preferably at least 97% wt.%, in particular at least 99 wt.% of the alcoholic solvent are removed by said distillation.
• hydrochloric acid is used in step (a), which is preferred according to the invention, part of the water from the hydrochloric acid, preferably at least 90 wt.%, more preferably at least 95 wt.%, most preferably at least 98% of the water from the hydrochloric acid, is also removed by said distillation.
• At least part of the pyridine base and at least part of the aromatic solvent having a boiling point of at least 160°C, preferably mesitylene, are added prior to the distillation of the alcoholic solvent.
• the alcoholic solvent used in step (a) is ethanol
• the pyridine base is 2-methyl-5-ethyl-pyridine
• the aprotic solvent used in step (b) is acetonitrile
• the aromatic solvent having a boiling point of at least 160°C used in step (b) is mesitylene.
• acetonitrile and mesitylene are preferably used in a ratio by weight of from 10:1 to 1:5, more preferably 5:1 to 1:2, and most preferably 3:1 to 1:1.
• the reaction is stopped (quenched) by means of another solvent exchange.
• the main portion of the solvent is preferably changed back from polar aprotic solvent to alcoholic solvent, wherein the alcoholic solvent used for the quench is preferably selected from ethanol, 1-butanol and 2-butanol, particularly preferred is ethanol.
• Said solvent exchange may be conducted by (i) distilling off a main portion of the aprotic solvent, preferably acetonitrile, and (ii) addition of an alcoholic solvent, preferably selected from ethanol, 1-butanol and 2-butanol, more preferably ethanol.
• the acetonitrile is removed by distillation and recycled, and the ethanol distillate obtained during the solvent exchange between steps (a) and (b) is re-used for the quench of the reaction giving the compound of formula (I).
• the compound of formula (I) can then be filtered off, washed with water and dried.
• the present invention also relates to a process for preparing fluoxapiprolin comprising the process for preparing the compound of the formula (I) according to the invention, and further comprising step (c) reacting the compound of the formula (I) obtained in step (b) with 3,5-bis(difluoromethyl)-1H-pyrazole.
• acetonitrile 127 g of acetonitrile are distilled off at 250 mbar. 253 g of technical ethanol are added and the temperature is reduced to 0°C. After stirring overnight, 150 g of water are added and stirring is continued for 2 h. The suspension is filtered and washed with a combination of 78:22 w/w acetonitrile/ethanol (30 g) and 50 g of ethanol.
• acetonitrile 131 g of acetonitrile are distilled off at 250 mbar. 121 g of technical ethanol are added and the temperature is reduced to 0 °C. After stirring overnight, 100 g of water are added and stirring is continued for 2 h. The suspension is filtered and washed with a combination of 78:22 w/w acetonitrile/ethanol (30 g) and 50 g of ethanol.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)
• Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Agricultural Chemicals And Associated Chemicals (AREA)

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• 2020
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